Inhalation of an increased concentration of carbon dioxide (CO2) has been shown to induce a state of negative affect in healthy subjects that is closely related to the clinical phenomenon of panic. It has been suggested that the vulnerability to CO2 is moderated by differences in serotonin (5-HT) activity, caused by a functional polymorphism in the promoter region of the 5-HT transporter (5-HTTLPR) gene. Our aim was to examine the relationship between bi- and tri-allelic 5-HTTLPR genotype and the affective response to different dosages of inhaled CO2 in healthy volunteers. Ninety-six subjects performed a double inhalation of four mixtures containing, respectively, 0%, 9%, 17.5% and 35% CO2, following a double-blind, cross-over, randomized design. Affective responses were measured with a visual analogue scale for fear and the Panic Symptom List. 5-HTTLPR genotype was expressed as LL, SL and SS. Subjects with the SL and SS genotype reported less fear than LL subjects. A significant interaction effect was found between genotype and CO2 dosage: the SS genotype showed lower fear scores than the LL genotype, particularly in the 17.5% CO2 dose condition. The present study suggests that the dose-dependent fear reaction to CO2 is moderated by a polymorphism in the 5-HT transporter gene, particularly at intermediate CO2 dosages. It also underscores the usefulness of the introduction of an intermediate phenotype related to panic to reveal an underlying genetic vulnerability otherwise staying elusive. These results are in line with current theories on the role of 5-HT in both panic and respiration.
American Psychiatric Association. (2000) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR, 4th edn. Washington, DC: American Psychiatric Association.
2.
BattagliaMPernaG. (1995) The 35% CO2 challenge in panic disorder: optimization by receiver operating characteristic (ROC) analysis. J Psychiatr Res29: 111–119.
3.
Ben-ZionIZMeiriGGreenbergBDMurphyDLBenjaminJ. (1999) Enhancement of CO2-induced anxiety in healthy volunteers with the serotonin antagonist metergoline. Am J Psychiatry156: 1635–1637.
4.
BlayaCSalumGALimaMSLeistner-SegalSManfroGG. (2007) Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and panic disorder: a systematic review and meta-analysis. Behav Brain Funct3: 41–41.
5.
GraeffFGDel-BenCM. (2008) Neurobiology of panic disorder: From animal models to brain neuroimaging. Neurosci Biobehav Rev32: 1326–1335.
6.
GraeffFGVianaMBMoraPO. (1997) Dual role of 5-HT in defense and anxiety. Neurosci Biobehav Rev21: 791–799.
HettemaJMNealeMCKendlerKS. (2001) A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry158: 1568–1578.
9.
HettemaJMPrescottCAMyersJMNealeMCKendlerKS. (2005) The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry62: 182–189.
10.
HuXZLipskyRHZhuG. (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet78: 815–826.
11.
KatonWJRoy-ByrnePRussoJCowleyD. (2002) Cost-effectiveness and cost offset of a collaborative care intervention for primary care patients with panic disorder. Arch Gen Psychiatry59: 1098–1104.
12.
KentJMCoplanJDMartinezJKarmallyWPappLAGormanJM. (1996) Ventilatory effects of tryptophan depletion in panic disorder: a preliminary report. Psychiatry Res64: 83–90.
13.
KesslerRCChiuWTJinRRuscioAMShearKWaltersEE. (2006) The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry63: 415–424.
14.
LeschKPBengelDHeilsA. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science274: 1527–1531.
15.
MaronEShlikJ. (2006) Serotonin function in panic disorder: Important, but why?Neuropsychopharmacology31: 1–11.
16.
MaronEToruITasaG. (2008) Association testing of panic disorder candidate genes using CCK-4 challenge in healthy volunteers. Neurosci Lett446: 88–92.
17.
MaronEToruIVasarVShlikJ. (2004) The effect of 5-hydroxytryptophan on cholecystokinin-4-induced panic attacks in healthy volunteers. J Psychopharmacol18: 194–199.
18.
Meyer-LindenbergAWeinbergerDR. (2006) Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci7: 818–827.
19.
MillerHEDeakinJFAndersonIM. (2000) Effect of acute tryptophan depletion on CO2-induced anxiety in patients with panic disorder and normal volunteers. Br J Psychiatry176: 182–188.
20.
MorenoFARoweDCKaiserB. (2002) Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion. Mol Psychiatry7: 213–216.
21.
MortimoreCAndersonIM. (2000) d-Fenfluramine in panic disorder: a dual role for 5-hydroxytryptamine. Psychopharmacology (Berl)149: 251–258.
22.
MunafoMRDurrantCLewisGFlintJ. (2009) Gene X environment interactions at the serotonin transporter locus. Biol Psychiatry65: 211–219.
23.
NakamuraMUenoSSanoATanabeH. (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry5: 32–38.
24.
NeumeisterAHuXZLuckenbaughDA. (2006) Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls. Arch Gen Psychiatry63: 978–986.
25.
ParkJWKimJSLeeHKKimYILeeKS. (2004) Serotonin transporter polymorphism and harm avoidance personality in chronic tension-type headache. Headache44: 1005–1009.
26.
PernaGdi BellaDFavaronECucchiMLiperiLBellodiL. (2004) Lack of relationship between CO2 reactivity and serotonin transporter gene regulatory region polymorphism in panic disorder. Am J Med Genet B Neuropsychiatr Genet129B: 41–43.
27.
PernaGFavaronEDi BellaDBussiRBellodiL. (2005) Anti-panic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene. Neuropsychopharmacology30: 2230–2235.
28.
RichersonGB. (2004) Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci5: 449–461.
29.
SanjuanJMartin-SantosRGarcia-EsteveL. (2008) Mood changes after delivery: role of the serotonin transporter gene. Br J Psychiatry193: 383–388.
30.
SchmidtNBStoreyJGreenbergBDSantiagoHTLiQMurphyDL. (2000) Evaluating gene x psychological risk factor effects in the pathogenesis of anxiety: a new model approach. J Abnorm Psychol109: 308–320.
31.
SchruersKGriezE. (2004) The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder. J Psychopharmacol18: 553–558.
32.
SchruersKKlaassenTPolsHOverbeekTDeutzNEGriezE. (2000) Effects of tryptophan depletion on carbon dioxide provoked panic in panic disorder patients. Psychiatry Res93: 179–187.
SeversonCAWangWPieriboneVADohleCIRichersonGB. (2003) Midbrain serotonergic neurons are central pH chemoreceptors. Nat Neurosci6: 1139–1140.
35.
SnijdersTABBoskerRJ. (1999) Multilevel Analysis: An Introduction to Basic and Advanced Multilevel Modeling. London: Sage.
36.
StataCorp. (2007) Stata Statistical Software: Release 10. College Station, TX: StataCorp LP.
37.
StrugLJSureshRFyerAJ. (2010) Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Mol Psychiatry15: 166–176.
van DuinenMRickeltJGriezE. (2008) Validation of the electronic Visual Analogue Scale of Anxiety. Prog Neuropsychopharmacol Biol Psychiatry32: 1045–1047.
40.
Van OsJShamP. (2003) Gene–environment interactions. In: MurrayRMJonesPBSusserEVan OsJCannonM (eds) The Epidemiology of Schizophrenia. Cambridge: Cambridge University Press, 235–254.
41.
VerburgKPernaGGriezEJL. (2001) A case study of the 35 % CO2 challenge. In: GriezEJLFaravelliCNuttDZoharJ (eds) Anxiety Disorders, an Introduction to Clinical Management and Research. Chichester: Wiley, 341–357.
42.
VerburgKPolsHde LeeuwMGriezE. (1998) Reliability of the 35% carbon dioxide panic provocation challenge. Psychiatry Res78: 207–214.
43.
WendlandJRMartinBJKruseMRLeschKPMurphyDL. (2006) Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry11: 224–226.
